Amino acids such as L-glutamic acid, L-aspartic acid are important as neurotransmitters for activation of nerve cells in central nervous system. However, excess accumulation of these excitatory amino acids in the exterior of the cells induces excess excitation of the nerve cells and is supposed to cause various cranial nervous diseases such as Parkinson's disease, senile dementia, Huntington chorea, and epilepsy as well as deletion of psychogenic and motor functions observed at the time of atmospheric hypoxia, ischemia and hypoglycemia, and head and spinal cord damages (reference to Non-patent Documents Nos. 1 and 2).
It has been known that the above-mentioned excitatory amino acids activate the central nerve cells through glutamate receptors existing in the nerve cells. Accordingly, the substances competitive with the excitatory amino acids for the binding to such receptors are supposed to be efficacious as medicaments for the diseases and symptoms as, for example, antiepileptic, ischemic cerebral damage preventive drugs, and antiparkinsonism drugs. Particularly, since a large quantity of glutamate is released by cranial ischemia such as cerebral infarction, the substances competitive for the glutamate receptors are supposed to be efficacious as the medicaments for an acute stage of cerebral infarction or the medicaments for chronic nerve degeneration diseases such as Alzheimer's disease.
The above-mentioned glutamate receptors can be classified into ionotropic and metabotropic receptors and theionotropic receptors can further be classified into three kinds based on the selectivity to agonists. They are called respectively as N-methyl-D-aspartic acid (NMDA) receptor, 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propanoic acid (AMPA) receptor, and kainate receptor.
Among them, the NMDA receptor is selectively activated by agonists such as glutamate, NMDA, ibotenic acid. The strong stimulus of the NMDA receptor induces large quantity of calcium influx to nerve cells and it is supposed to be one of causes of nerve degeneration cell death. Recently, cloning of genes of the NMDA receptor has been done from brains of rats and mice to make it clear that the NMDA receptor is composed of two subunits of NR1 and NR2 (reference to Non-patent Documents Nos. 3 and 4). The NR2 subunit contains four subfamilies (NR2A, 2B, 2C, and 2D) (reference to Non-patent Document Nos. 5 and 6). It is said that the NR1/NR2A receptors are mainly relevant to development of memory and learning acquirement and that the NR1/NR2B receptor is mainly relevant to nerve degeneration cell death and transmittance of pains (reference to Non-patent Document Nos. 7 and 8).
Those conventionally known as NMDA receptor antagonists are 1) drugs for binding to the subfamilies of the NR1/NR2 receptor competitively with agonists such as glutamate and NMDA (hereinafter, referred to as competitive NMDA receptor antagonists, e.g. D-2-amino-5-phosphonovaleric acid) and 2) drugs for inhibiting calcium influx in nerve cells by non-competitive binding to the NMDA receptor irrelevantly to the agonist such as glutamate and NMDA (hereinafter, referred to as non-competitive NMDA receptor antagonists, e.g. MK-801 (Patent Document No. 2)).
However, since the competitive NMDA receptor antagonists may possibly antagonize not only the NR1/NR2B receptor but also NR1/NR2A receptor, in the case of long time administration of the drugs for Alzheimer's disease or the like, there is a risk of deterioration of learning capability and memory formation.
Also, in recent years, morphine has been used widely for the treatment of cancer pains and other analgesics and adjuvant analgesics drugs have been used for alleviating the pains on which morphine is not efficacious and suppressing the side effects (Non-patent Document No. 9)
Ketamine is known as such an analgesic and since it is a non-competitive NMDA receptor antagonist, it is known that ketamine sometimes causes psychological dependency and psychosis (e.g. schizophrenia) as a side effect.
On the other hand, Ifenprodil, which is a cerebral circulation improvement drug, shows high affinity to the NR1/NR2B receptor and enhances the morphine-derived analgesic effect. CP-101606, which is a competitive NMDA receptor antagonist, shows selective antagonistic action to the NR1/NR2B receptor and is known to be effective for Parkinson's disease, stroke, migraine, tinnitus, head injury (reference to Patent Document No. 1). These drugs showing high affinity with the NR1/NR2B receptor may highly possibly be analgesics with less side effects on the motor function (e.g. paresthesia), psychosis (e.g. schizophrenia).
Patent Document No. 3 discloses a compound having an analogous structure with that of a piperidine derivative of the present invention and having antagonistic action to NMDA; however, a compound having a hydroxy group as a substituent for R3 of the compound of the present invention is not disclosed. Patent Document Nos. 4 to 6 disclose compounds having analogous structures with that of a piperidine derivative of the present invention; however, there is no practical description of the NMDA receptor antagonistic action.
Patent Document No. 7 discloses a compound having an analogous structure with that of a piperidine derivative of the present invention; however, the selectivity for the subtype of the NMDA receptor is low or the activity is not high.    [Patent Document No. 1] U.S. Pat. No. 5,338,754    [Patent Document No. 2] U.S. Pat. No. 4,232,158    [Patent Document No. 3] WO 96/02250    [Patent Document No. 4] JP 1986-36262 A    [Patent Document No. 5] WO 91/08200    [Patent Document No. 6] UK 881,894    [Patent Document No. 7] WO 03/035641    [Non-patent Document No. 1] NATURE (1976), vol. 263, p. 517    [Non-patent Document No. 2] NATURE (1991), vol. 349, p. 414    [Non-patent Document No. 3] NATURE (1992), vol. 357, p. 70    [Non-patent Document No. 4] NATURE (1992), vol. 358, p. 364    [Non-patent Document No. 5] SCIENCE (1992), vol. 256, p. 1217    [Non-patent Document No. 6] FEBS LETT (1992), vol. 300, p. 39    [Non-patent Document No. 7] STROKE (1997), vol. 28, p. 2244    [Non-patent Document No. 8] TRENDS PHARMA SCI (2001), vol. 22, p. 636    [Non-patent Document No. 9] Journal of Japanese Pharmacological Society (2001), vol. 117, p. 13